Synthesis of quinoline acetohydrazide-hydrazone derivatives evaluated as DNA gyrase inhibitors and potent antimicrobial agents

Abstract

E)-N'-(substituted-benzylidene)-2-(7-fluoro-2-methoxyquinolin-8-yl) acetohydrazide-hydrazone derivatives reported in this manuscript represents a new series of antibacterial agents as well as the DNA gyrase inhibitors. Efforts were made to synthesize these quinolone-acetohydrazide-hydrazone derivatives (9a-n) in excellent yields. All the target compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424) as specimens for Gram-negative bacteria, and Staphylococcus aureus (MTCC 96) and Staphylococcus pyogenes (MTCC 442) as specimens for Gram-positive bacteria. Excellent antibacterial activity was observed for compounds substituted with R=3,4,5-trimethoxy, 4-F, 4-OCF3, 4-CF3 , 3-CF3 moieties. Derivatives 9a-n were docked into the active sites of DNA gyrase A and DNA gyrase B in order to get more insight into the binding mode of the compounds. Among all derivatives, 9n showed a least binding energy as -91.6 kcal/mol was the best among all compounds for DNA gyrase A. DNA gyrase enzyme inhibtion assay favors the compound 9m and 9n, which were substituted with di-fluorine moieties (R = 2,4difluoro and 3,4-difluoro) in the quinoline scaffold, as the most potent inhibitors with of S. aureus DNA gyrase A (9mIC50 0.14 mg/mL and 9nIC50 0.19 mg/mL).

Computational Approaches to Develop Isoquinoline Based Antibiotics through DNA Gyrase Inhibition Mechanisms Unveiled through Antibacterial Evaluation and Molecular Docking

“…The DNA gyrase A (S.aureus) assay of compounds (5a-h) was carried out as we reported earlier. [28] DNA gyrase purification, supercoiling, and decatenation were executed as reported by F. Blanche 1996. [34]…”

“…In order to evaluate the DNA gyrase inhibition assay, the bacterial strain S. aureus (MTCC 96) was sub‐cultured in medium B (2 g yeast extract, 10 g polypeptone, 1.2 g (NH 4 ) 2 SO 4 , 8 g Na 2 HPO, 2 g KH 2 PO 4 , 0.2 g MgSO 4 , 4 g glucose in 1 L distilled water). The DNA gyrase A ( S.aureus ) assay of compounds (5a–h) was carried out as we reported earlier . DNA gyrase purification, supercoiling, and decatenation were executed as reported by F. Blanche 1996 …”

Synthesis, Characterization, Antibacterial and Antifungal Evaluation of Novel Cyclohexanone Benzoylhydrazones

“…No phenolic O-H streching vibrations were observed in the IR spectra of the hydrazide (1) or hydrazones (2a-j). Absence of the O-H bands in the expected regions is presumably due to the strong intramolecular hydrogen bonding between the phenolic O-H and C=O groups (Silverstein et al 2005). The resonances of the -OCH 3 group and aromatic hydrogens were observed in the δ 3.76-3.77 ppm and δ 6.46-7.89 ppm, respectively.…”

N‐substituted hydroxynaphthalene imino‐oxindole derivatives as new class of PI3‐kinase inhibitor and breast cancer drug: Molecular validation and structure–activity relationship studies

“…Autodock 4.2.6 and Autodock Tools (ADT) 1.5.6. were used for the docking studies . Their 3D atomic co‐ordinates of N‐substituted hydroxynaphthalene imino‐oxindole derivatives ( 5a–g ) were created using ACD/Labs— Chemsketch 12.0 software.…”

“…The absorbance was measured at 570 nm, and the cell viability was calculated using the following formula, 2.6 | Molecular docking studies autodoCk 4.2.6 and Autodock Tools (ADT) 1.5.6. were used for the docking studies. [23][24][25][26][27][28][29][30][31][32][33] Their 3D atomic co-ordinates of N-substituted hydroxynaphthalene imino-oxindole derivatives (5a-g) were created using ACD/Labs-ChemSketCh 12.0 software. Geometries of compounds (5a-g) were cleaned and generated as the corresponding pdb.…”